In the past decade, the research in Dr. Domburg?s laboratory has been focused on the development of cell-type-specific retroviral vectors, derived from the avian reticuloendotheliosis viruses, spleen necrosis virus, SNV, and reticuloendotheliosis virus strain A, REV-A. Cell-type-specific retroviral vector particles have been developed, which enable highly efficient gene transduction into cells of the human hematopoietic system. Modifications in the matrix (MA) protein of SNV and REV-A enabled gene transduction of quiescent hematopoietic cells. Using SCID mice and subcutaneous tumors as a model, our preliminary data suggest that a target cell specific gene delivery can be obtained in vivo with SNV-derived retroviral vectors implanted in Theracyte immunoisolation devices. We will continue to use this current model system to further evaluate (i) the duration and efficiency of the gene transfer and (ii) to establish selected packaging cells lines selected and optimized for efficient in vivo gene delivery through Theracyte implantation bags (Specific Aim #1). New vector systems will be developed which will enable to expand our studies with Theracyte immunoisolation devices using (i) hu- PBL-SCID mice and human hematopoietic cells as targets and (ii) mice models for gene delivery into neuronal cells. Helper cells will be implanted in Theracyte devices transducing novel vectors (Specific Aim #2) to evaluate the efficiency of the gene transfer and the expression of therapeutic genes in infected cells in vivo. The human hematopoietic cells will be recovered from various organs in the mouse, eg., the spleen or lymph nodes for the evaluation of the gene transfer. In another approach we will use immunocompetent mice and rats to investigate (i) immune responses against the helper cells and vector particles and (ii) test whether retroviral vectors specific for neuronal cells can be delivered to the brain through Theracyte implantation bags (Specific Aim #3).